targeted therapies for hepatocellular carcinoma universitätsklinik für innere medizin iii klin....
DESCRIPTION
HEPATOCELLULAR CARCINOMA INCIDENCE rising incidence worldwide most frequent malignancy Austria 9 / % of all tumors Bosch et al. Sem.Liv.Dis. 1999; 19:TRANSCRIPT
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TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA
Universitätsklinik für Innere Medizin IIIKlin. Abtl. für Gastroenterologie und Hepatologie
Christian Müller
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TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA
Universitätsklinik für Innere Medizin IIIKlin. Abtl. für Gastroenterologie und Hepatologie
Christian Müller
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HEPATOCELLULAR CARCINOMA
INCIDENCE
rising incidence
worldwide most frequent malignancy
Austria 9 / 100.000 2% of all tumors
0 10 20 30 40 50age-adjusted incidence rates
Northern Europe
Australia
Southern Asia
South America
North America
Northern Africa
Western Europe
Western Asia
Estern Europe
Central America
The Caribbean
Southern Europe
South-Eastern Asia
Pacific Islands
Eastern Africa
Southern Africa
Western Africa
Central Africa
Eastern Asia
Bosch et al. Sem.Liv.Dis. 1999; 19: 271-285.
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HEPATOCELLULAR CARCINOMAETIOLOGY OF LIVER DISEASE
Anti-HCV+ 94 38%HBsAg+ 28 11%ALCOHOLIC 86 35%HEMOCHROMATOSIS 10 4%PBC 2 1%CRYPTOGENIC 29 12%
38%
11%
35%
4%1%12%
alcoholic
Anti-HCV +
HBsAg +
hemochromatosis
PBCcryptogenic
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HCC
STAGE 0Very early
1 HCC < 2 cmCHILD A PST 0
STAGE AEarly
1 HCC < 5 cm or <3 HCC < 3 cmCHILD A/B PST 0
STAGE BIntermediate
MultinodularCHILD A/B PST 0
STAGE CAdvanced
Portal Invasion, N1,M1CHILD A/B PST 1-2
STAGE DTerminal
Portal Invasion M1,N1CHILD C,PST >2
BCLC HCC STAGING AND TREATMENT
Portal Pressure / Bilirubin
Associated Diseases
Resection LTX PEI / RFA
normal
increased
no yes
TACE Sorafenib
Potentially Curative Treatment5-year survival 50-70%
Palliative Treatment – RCTMedian survival (untreated) 5-16 mo
SupportiveTreatment
Survival < 3 mo
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SORAFENIB IN HCC TREATMENT - RATIONALE
RAF kinase overexpressed and activated in HCC
RAF / MEK / ERK signaling pathway implicated in liver
tumorigenesis
Sorafenib is a multikinase inhibitor of RAF, VEGFR, and
other kinases
Sorafenib induces apoptosis in HCC xenograft models
Sorafenib active in Phase II trial of patients with
advanced HCC and CHILD A / B liver function
Hwang et al. Hepatol Res 2004;29:113-121Calvisi et al. Gastroenterology 2006;130:1117-1128Villanueva et al. Semin Liv Dis 2007; 27:55-76Liu et al. Cancer Res 2006; 66:11851-11858Abou-Alfa et al. J Clin Oncol 2006; 24: 4293-4300
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RAS
Endothelial cell or Pericyte
Angiogenesis:
PDGF- VEGF
VEGFR-2PDGFR-
Paracrine stimulation
Mitochondria
Apoptosis
Tumor cell
PDGFVEGF
EGF/HGF
ProliferationSurvival
Mitochondria
EGF/HGF
HIF-2
Nucleus
Autocrine loop
Apoptosis
ERK
RAS
MEK
RAF
Nucleus
ERK
MEK
Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis
Wilhelm S et al. Cancer Res. 2004;64:7099-7109
RAF
DifferentiationProliferationMigrationTubule formation
Sorafenib
Sorafenib
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PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC
STUDY DESIGN
PRIMARY END-POINT: OVERALL SURVIVALTIME TO SYMPTOMATIC PROGRESSION
SECONDARY END-POINTS: TIME TO PROGRESSION
Stratification:
Macroscopic vascular invasion and / or
extrahepatic spread
ECOG PS
Geographic region Rand
omiz
atio
n
n =
602
Sorafenib (n=299)400 mg po bid
Continous dosing
Placebo (n=303)2 tablets po bid
Continous dosing
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SorafenibMedian: 46.3 weeks(95% CI: 40.9, 57.9)
Surv
ival
Pro
babi
lity
Weeks
Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P=0.00058*
PlaceboMedian: 34.4 weeks (95% CI: 29.4, 39.4)
1.00
0
0.75
0.50
0.25
0 808 16 24 32 40 48 56 64 72
0274 241 205 161 108 67 38 12 0Patients at risk
Sorafenib:0276 224 179 126 78 47 25 7 2Placebo:
299303
PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC
OVERALL SURVIVAL
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0196 126 80 50 28 14 8 20192 101 57 31 12 8 2 1
Pro
babi
lity
of p
rogr
essi
on
Hazard ratio (S/P): 0.58 . (95% CI: 0.44, 0.74) P=0.000007
546 12 18 24 30 36 42 480 Weeks
SorafenibMedian: 24.0 weeks(95% CI: 18.0, 30.0)PlaceboMedian: 12.3 weeks(95% CI: 11.7, 17.1)
1.00
0
0.75
0.50
0.25
Patients at risk Sorafenib:
Placebo:299303
PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC
TIME TO PROGRESSION
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PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC
Baseline characteristics of patientsCharacteristics Sorafenib Placebo
(n=299) (n=303)
Age (vears,median) 65 66Male / Female (%) 87 / 13 87 / 13Region (Europe / N.America / others;%) 88 / 9 / 3 87 / 10 / 3Etiology (%)
HCV / HBV 29 / 19 27 / 18Alcohol / other 26 / 26 26 / 29
Child (A / B; %) 95 / 5 98 / 2Prior Therapies (%):
Resection 19 21PAI / RFA / TACE 39 41
BCLC stage (%) Stage B 18 17Stage C 82 83
ECOG PS (%)ECOG 0 54 54ECOG 1 38 39ECOG 2 8 7
Vascular Invasion /Extrahepatic spread (%) 70 70
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PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC
Safety eventsSorafenib Placebo
(n=299) (n=303)
Serious adverse events (SAE;%) 52 54
Adverse events (%) all grade 3/4 all grade 3/4
Diarrhea 39 8/- 11 2/-Pain (abdomen) 8 2/- 3 <1/-Weight loss 9 2/- <1 0/-Anorexia 14 <1/- 3 <1/-Nausea 11 <1/- 8 1/-Hand-foot skin reaction 21 8/- 3 <1/-Vomiting 5 1/- 3 <1/-Alopecia 14 0/- 2 0/-Liver dysfunction <1 <1/- 0 0/-Bleeding 7 <1/- 4 <1/<1
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Sorafenib plus doxorubicin in patients with advanced HCCO
S (%
pts
)
Time from randomisation (mo)0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Median OS (Phase II)Doxorubicin + sorafenib: 13.7 months(95% CI: 10.4–can not be estimated)
100
75
50
25
0
Doxorubicin + placebo: 6.5 months (95% CI: 4.9–9.5)HR=0.45; p=0.0049
Censored treatment
Abou-Alfa GK. ECCO 2007
OVERALL SURVIVAL
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HCC
STAGE 0Very early
1 HCC < 2 cmCHILD A PST 0
STAGE AEarly
1 HCC < 5 cm or <3 HCC < 3 cmCHILD A/B PST 0
STAGE BIntermediate
MultinodularCHILD A/B PST 0
STAGE CAdvanced
Portal Invasion, N1,M1CHILD A/B PST 1-2
STAGE DTerminal
Portal Invasion M1,N1CHILD C,PST >2
BCLC HCC STAGING AND TREATMENT
Portal Pressure / Bilirubin
Associated Diseases
Resection LTX PEI / RFA
normal
increased
no yes
TACE New Agents
Potentially Curative Treatment5-year survival 50-70%
Palliative Treatment – RCTMedian survival (untreated) 5-16 mo
SupportiveTreatment
Survival < 3 mo
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Targeted agents in development for HCC
AgentAnti-angiogenic targets Antiproliferative targets Developmental status
VEGF VEGFR PDGFR EGFR Raf mTOR
Bevacizumab ● Phase II ongoing
Brivanib ● Phase II recruiting
Cediranib ● Phase II recruiting
Erlotinib ● Phase II complete
Gefitinib ● Phase II complete
Cetuximab ●Lapatinib ● Phase II ongoing
RAD001 ● Phase I/II recruiting
Sorafenib* ● ● ● Phase III complete
Sunitinib* ● ● Phase II ongoing
Thalidomide ● Phase III recruiting
TSU-68 ● ● Phase I/II recruiting
Phase II complete
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Faivre SJ, et al. ASCO 2007
Sunitinib in patients with unresectable HCC
• Patients (n=37) sunitinib 50mg daily for 4 weeks, 2 weeks pause• Major (≥50%) tumour necrosis: 46% of patients• Response (RECIST)
– PR: 1 pt (3%) – SD >3 months: 13 pts (35%)– SD >6 months: 8 pts (22%)
• Grade 3–4 toxicities:thrombocytopenia (43%)neutropenia (24%) CNS symptoms (24%) asthenia (22%) haemorrhage (14%)
Grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure)
Grade 1–2 skin toxicity frequently reportedDose reductions: 27% of patients
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• 38 pts erlotinib 150mg daily • Median OS: 13 months• PFS: 3 months• Grade 3–4 Aes: 61% of patients (skin rash [13%], diarrhoea [8%] and fatigue [8%])
Erlotinib in patients with advanced HCC
Philip PA. J Clin Oncol 2005;23:6657–63
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27 30
Follow-up (months)
Pati
ents
(%
)
OSPFS
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Summary
• Several targeted agents, either alone or in combination with other therapies, have shown promising efficacy and tolerability in phase II trials of patients with advanced HCC
• Randomised, phase III trials, with sorafenib as an active comparator, will be required to optimise targeted therapy of HCC in the future
• Sorafenib standard treatment in advanced HCC (BCLC stage C) and well preserved liver function (Child A). Prolongs TTP and survival (Phase III study)
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Studies with other targeted therapeutic agents in advanced HCC
• Thalidomide
• Cetuximab (Erbitux; EGFR-Ak)
• Bevacizumab (Avastin; VEGF-AK) Bevacizumab + Erlotinib
Bevacizumab + Capecitabine
• Perifosine (Akt- Inhibitor)
• Erlotinib (Terceva; EGFR Thyrosinkinase-Inhibitor)
• Gefitinib (Iressa; EGFR Thyrosinkinase-Inhibitor)
• Lapatinib (Tyverb; EGFR Thyrosinkinase-Inhibitor)
• 32 pts cetuximab 400 mg / m2 loading dose +
250 mg / m2 i.v. weekly
• 27 pts evaluable for tumour response– SD ≥8 weeks: 12 pts (44.4%)
• Median time to progression (TTP): 8 weeks – median TTP in pts with SD ≥8 weeks: 22.5 weeks
• No treatment-related severe AEs noted